Human breast tumors show great diversity in their morphologies, natural histories and in their responses to therapy. This wide tumor diversity" poses one of the central challenges to the accurate diagnosis, prevention and treatment of breast tumors. We have used genome-wide gene expression profiling and found that infiltrating ductal and lobular carcinomas of the breast segregated into five distinct and reproducible subtypes [1, 2]. Included within these five subtypes was a new class of tumors that was Estrogen Receptor (ER) and HER2 negative, and which showed characteristics of breast basal/myoepithelial cells. We next demonstrated that this "basal-like" subtype had on average, the fastest proliferation rates and the shortest overall patient survival times [2]. The development of a prevention strategy for this deadly type of breast tumor is needed because of the unique clinical and biological properties of these tumors. We propose to characterize human basal-like tumors using cellular and genetic assays in order to identify the molecular alterations that are present within this subtype as a first step towards the prevention of this ER-negative subtype of breast tumor. Next, we will determine if breast basal-like tumors progress through a Carcinoma In Situ (CIS) stage, and determine if the most common chemoprevention targets are ever present within these tumors or their precursor lesions. Finally, we will expression profile mouse mammary tumors and compare these results to our human data to identify murine models of basal like tumors, and to identify targets that are present in both hormonally non-responsive animal models and in basal-like tumors of humans.